Loss of smell is one of the first signs of many neurodegenerative diseases and aging disorders. Knowledge of neuronal structure and the pathways of information flow in the brain is important for identifying the cause of smell loss in diseased brains which may lead to early diagnosis and better treatment of the underlying conditions. Studies in the past have uncovered much about the mechanisms of odor detection in the mouse olfactory epithelium and bulb, but little is known about how sensory information is encoded in the cortex. We previously showed that inputs derived from different types of odorant receptors (ORs) are targeted to different but spatially overlapping clusters of cortical neurons and each cortical neuron appears to receive inputs from multiple ORs. Given that each odor molecule is detected in the nose by a combination of different ORs, this proposal will develop and apply genetic and functional approaches to test if inputs from the different ORs activated by the same odorant converge on cortical neurons to determine their response specificity. In Aim 1, we will develop recombinant adeno-associated virus (rAAV) to express different transneuronal tracers. As each bulb glomerulus represents a single type of OR, we will inject different rAAVs into different glomeruli to express a distinct tracer in bulb mitral and tufted cells connected to the injected glomeruli. The tracer will migrate from bulb to cortex to reveal the cortical organization of the corresponding ORs. These studies will test if inputs from the ORsactivatedby the same odorant converge on cortical neurons. In Aim 2, we will examine if the neurons activated by an odorant are those that receive convergent inputs from its ORs. In addition, we will compare the cortical neurons activated by separate versus combined OR inputs to test if combinations of ORinputs shape the response specificity of cortical neurons. Together, these studies will show how different chemical features detected by different ORs are integrated in the cortex to yield distinct perceptions. The new tracing method developed in this proposal will also be useful to systematically analyze how the stereotyped bulb map is topographically represented in the cortex and if different odor qualities are represented by distinct cortical patterns. The proposed studies are ideally suited fortheR21 mechanism.